Human DNA sequence differs among individuals and the most common variations are known as single nucleotide polymorphisms, or SNPs. Studies have shown that non-synonymous coding SNPs (nsSNPs - SNPs occurring in protein coding regions which lead to amino acid substitutions) can be responsible for many human diseases. X-linked mental retardation (XLMR) is a particular example of a group of heterogeneous conditions with an estimated frequency of 5-12% in the mentally retarded populations. Specifically, in this proposal we focus on XLMR caused by a defect in spearmine synthase (SMS). Polyamines are ubiquitous molecules that interact with variety of other molecules in the cell and are essential for normal cell growth and differentiation. Especially spearmine have been shown to modulate ion channel activities is particular cells. In this proposal we will investigate three nsSNP within SMS known to cause XLMP to reveal the molecular mechanism of effect of mutations on structure, function and interactions of SMS. Three nsSNPs (G56S, V132G and I150T) in the spearmine sythase gene that encodes a protein of 366 amino acids were shown to be responsible for XLMR by our collaborator Dr. Schwartz and co-workers. However, no explanation of the effects on molecular level is available. Therefore, further investigation of these variants by combined efforts of computational modeling at molecular level with experimental investigations in Dr. Schwartz lab will provide valuable information of the molecular basis of how these snSNP affect the spearnime synthase stability, function and interactions. The outcome of the proposed research has the potential to provide valuable insights towards understanding the cause of the disease. The project will enable PI's lab to enter the field of the clinical research by collaborating with the Greenwood Genetic Center (Dr. Charles Schwartz). The results of the computational modeling will be used to generate testable hypothesizes and other still unknown missense mutations will be suggested. These hypotheses and mutants will be biochemically tested in Dr. Schwartz lab and screened against available clinical data.